Title
Possible role of p53/Mieap-regulated mitochondrial quality
control as a tumor suppressor in human breast cancer( 内容と審
査の要旨(Summary) )
Author(s)
SIQINGAOWA
Report No.(Doctoral
Degree)
博士(医学) 甲第1105号
Issue Date
2019-04-17
Type
博士論文
Version
ETD
URL
http://hdl.handle.net/20.500.12099/78432
※この資料の著作権は、各資料の著者・学協会・出版社等に帰属します。Ặ ྡ 㸦 ᮏ ⡠ 㸧 SIQINGAOWA 㸦୰ ᅜ 㸧 Ꮫ ࡢ ✀ 㢮 ༤ ኈ㸦་Ꮫ㸧
Ꮫ ᤵ ␒ ྕ ⏥➨1105 ྕ
Ꮫ ᤵ ᪥ ᖹᡂ31 ᖺ 4 ᭶ 17 ᪥ Ꮫ ᤵ せ ௳ Ꮫつ๎➨㸲᮲➨㸯㡯ヱᙜ
Ꮫ ㄽ ᩥ 㢟 ┠ Possible role of p53/Mieap-regulated mitochondrial quality control as a tumor suppressor in human breast cancer
ᑂ ᰝ ጤ ဨ 㸦ᰝ㸧ᩍᤵ ΎỈ 㞞ோ 㸦ᰝ㸧ᩍᤵ ୰ᓥ ⱱ ᩍᤵ ཎ ᫂ ㄽ ᩥ ෆ ᐜ ࡢ せ ᪨ ࠙⥴ゝࠚ S ࡣ㌿ᅉᏊࡋ࡚ከᵝ࡞ୗὶ㑇ఏᏊࡢⓎ⌧ࢆไᚚࡋ㸪⒴ᢚไാ࠸࡚࠸ࡿࠋS ࡢୗὶ㑇ఏᏊ ࡛࠶ࡿ0LHDS㸦0LWRFKRQGULDHDWLQJSURWHLQ㸧ࡣ㸪ࣜࢯࢯ࣮࣒ᵝࢱࣥࣃࢡ㉁ࢆ㞟✚ࡉࡏ㸪㧗ࣞ࣋ࣝ ࡢάᛶ㓟⣲✀㸦526㸧ࢆ⏘⏕ࡍࡿⰋ࡞࣑ࢺࢥࣥࢻࣜࡢᶵ⬟ࢆಟ࣭ᨵၿࡍࡿࡇ㸦0LHDSLQGXFHG DFFXPXODWLRQRIO\VRVRPHOLNHRUJDQHOOHVZLWKLQPLWRFKRQGULD㸸0$/0㸧㸪ࡲࡓᕧ࡞ᾮ⬊ᵝࡢᵓ 㐀≀ࢆᙧᡂࡋ㸪ရ㉁ࡢຎࡋࡓ࣑ࢺࢥࣥࢻࣜࢆࡇࡢᵓ㐀≀ྲྀࡾ㎸ࢇ࡛ศゎ࣭㝖ࡍࡿࡇ 㸦0LHDSLQGXFHGYDFXROH㸸0,9㸧ࡀሗ࿌ࡉࢀ࡚࠸ࡿࠋࡍ࡞ࢃࡕ 0LHDS ࡣ㸪⣽⬊ෆࡢ 526 ࣞ࣋ࣝࢆୗ ࡆ㸪࣑ࢺࢥࣥࢻࣜࡢရ㉁⟶⌮㸦0LWRFKRQGULDTXDOLW\FRQWURO 04&㸧ࢆ⾜࠺ࡇ࡛⒴ᢚไຠᯝࢆ Ⓨࡍࡿࡇࡀ▱ࡽࢀ࡚࠸ࡿࠋ࣐࢘ࢫࣔࢹࣝ࠾࠸࡚ࡶ㸪0LHDS ࡀ⭠⟶ࡢ࣏࣮ࣜࣉࡸ⒴ࡢⓎ⏕ᢚ ไⓗാࡃࡇࡀ♧ࡉࢀ࡚࠸ࡿࡀ㸪ࡑࡢࡢ⒴⭘࠾ࡅࡿ 0LHDS ࡢ⭘⒆ᙧᡂᢚไᶵᗎࡘ࠸࡚ࡣ༑ ศゎ᫂ࡉࢀ࡚࠸࡞࠸ࠋᮏ◊✲࡛ࡣ㸪ங⭢⭘⒆࠾ࡅࡿ 0LHDS ࡢⓎ⌧ࡑࡢព⩏ࡘ࠸᳨࡚ウࡋࡓࠋ ࠙ᑐ㇟᪉ἲࠚ ձ 0LHDS ࡢⓎ⌧ࡀங⒴⣽⬊ᰴࡢ࣏ࢺ࣮ࢩࢫ࠼ࡿᙳ㡪㸸0LHDS Ⓨ⌧ࢹࣀ࢘ࣝࢫࢆ⏝࠸࡚㸪 ங⒴⣽⬊ᰴ㹹6.%5㸦+(5W\SH㸧㸪0&)㸦/XPLQDOW\SH㸧㸪0'$0%㸦7ULSOHQHJDWLYH㸧㹻 0LHDS ࢆᙉไⓎ⌧ࡉࡏ㸪ྛ⣽⬊ᰴࡢ⣽⬊࿘ᮇ㸦)$&6㸧㸪࢝ࢫࣃ࣮ࢮࡢάᛶ㸦࢝ࢫࣃ࣮ࢮࢵࢭ 㸧㸪FDVSDVH ࡞࣏ࢺ࣮ࢩࢫ㛵㐃ࢱࣥࣃࢡ㉁ࡢኚ㸦࢚࢘ࢫࢱࣥࣈࣟࢵࢸࣥࢢἲ㸧 ࢆほᐹࡋࡓࠋ ղࣄࢺங⒴᳨య࠾ࡅࡿ 0LHDSࡢⓎ⌧㛵ࡍࡿ᳨ウ㸸ᙜ㝔࡛ษ㝖ࢆ⾜ࡗࡓᾐ₶ᛶங⟶⒴ ,'&㸸 㸪㠀ᾐ₶ᛶங⟶⒴ '&,6㸸 㸪⥺⥔⭢⭘ )$㸸 ࡢᡭ⾡ᶆᮏࢆ⏝࠸࡚㸪ᢠ 0LHDS ᢠయ ࡼࡿච⤌⧊ᰁⰍࢆ⾜ࡗࡓࠋ ճ04& ⤒㊰㸦S0LHDS%1,31,;㸧ࡢ␗ᖖங⟶⒴ᝈ⪅ࡢணᚋ㛵ࡍࡿ᳨ウ㸸,'& ࡘ࠸࡚㸪 0LHDS࠾ࡼࡧ FRIDFWRU ࡛࠶ࡿ%1,3ࡸ1,;ࣉ࣮ࣟࣔࢱ࣮ࡢ '1$ ࣓ࢳࣝࡢ᭷↓ࢆ࣓ࢳࣝ 3&5 ࡚㸪S㑇ఏᏊࡢኚ␗ࡢ᭷↓㸦([RQ㸧ࢆࢲࣞࢡࢺࢩ࣮ࢡ࢚ࣥࢫἲ࡚ࡑࢀࡒࢀ᳨ウࡋࡓࠋ ࠙⤖ᯝࠚ ձ0LHDS ࡢᙉไⓎ⌧ࡼࡗ࡚㸪࠸ࡎࢀࡢ⣽⬊ᰴ࡛ࡶ '1$ ᩿∦ࢆ♧ࡍ VXE* ࡢቑຍࡀぢࡽࢀࡓࡀ㸪 0'$0% ࡛ࡣࡑࡢྜࡀపࡗࡓࠋࢹࣀ࢘ࣝࢫឤᰁ 㛫௨㝆㸪࡚ࡢங⒴⣽⬊ᰴࡢ
⣽⬊㉁ࣜࢯࢯ࣮࣒ᵝࡢ 0,9 ࡀฟ⌧ࡋࡓࠋ6.%5 ⣽⬊ᰴ࡛ࡣ㸪0LHDS ࢆⓎ⌧ࡉࡏࡓ 㛫௨ᚋ FDVSDVH ࠾ࡼࡧ FDVSDVH ࡢάᛶࡀぢࡽࢀࡓࠋ0&) ⣽⬊ᰴ㸦FDVSDVH Ḟᦆᰴ㸧࡛ࡣ FDVSDVH ࡢࡳࡢάᛶࡀぢࡽࢀࡓࠋ୍᪉㸪0'$0% ࡛ࡣ࢝ࢫࣃ࣮ࢮࡢάᛶ㸪3$53 ࡢ᩿∦ ࡣㄆࡵ࡞ࡗࡓࠋ ղචᰁⰍ࡚ 0LHDS ࡣ⣽⬊㉁Ⓨ⌧ࡀㄆࡵࡽࢀࡓࠋ,'&㸪'&,6㸪)$ ࠾ࡅࡿ 0LHDS 㝧ᛶ⋡ࡣ㸪ࡑ ࢀࡒࢀ 㸦㸧㸪㸦㸧㸪 㸦㸧࡛࠶ࡾྛ⩌㛫࡛᭷ពᕪࢆㄆࡵࡓࠋ,'& ࡼࡾ '&,6 ࡸ )$ ࡢ᪉ࡀ᭷ព㝧ᛶ⋡ࡣ㧗ࡗࡓ㸦,'&YV'&,6㸸S 㸪'&,6YV)$㸸S 㸪 ,'&YV)$㸸S 㸧ࠋ ճ,'& ࡢ ࡢ࡛0LHDSࣉ࣮ࣟࣔࢱ࣮ࡢ࣓ࢳࣝ㸪ࡢ࡛S㑇ఏᏊࡢኚ␗ࡀㄆࡵࡽࢀ㸪 S0LHDS ࡼࡿ 04& ⤒㊰␗ᖖࢆ᮶ࡋ࡚࠸ࡓࠋࡲࡓ㸪S0LHDS ⤒㊰␗ᖖࡢ࠶ࡿங⒴ࡣ↓ Ⓨ⏕Ꮡᮇ㛫ࡀ᭷ព▷⦰ࡋ࡚࠸ࡓ㸦S 㸧ࠋ ࠙⪃ᐹࠚ ங⒴⣽⬊䛻 0LHDS ࢆᙉไⓎ⌧ࡉࡏࡿ㸪࢝ࢫࣃ࣮ࢮ౫Ꮡᛶࡢ࣏ࢺ࣮ࢩࢫࡀㄏᑟࡉࢀࡓࠋ࢝ࢫࣃ ࣮ࢮࡢάᛶࣞ࣋ࣝ㸦≉࢝ࢫࣃ࣮ࢮ 㸧ࡣ㸪࣏ࢺ࣮ࢩࢫࡢ⛬ᗘࡁࡃ┦㛵ࡋ࡚࠸ࡓࠋࡍ ࡞ࢃࡕ 㻹㼕㼑㼍㼜 䛿㸪0$/00,9 ࢆࡋࡓ 04& ࡢไᚚࡢࡳ࡞ࡽࡎ㸪࣏ࢺ࣮ࢩࢫࡢㄏᑟࡼࡗ࡚┤᥋ⓗ ங⒴⣽⬊䛻⣽⬊Ṛࢆㄏᑟࡍࡿࡇࡀ᫂ࡽ࡞ࡗࡓࠋࣄࢺங⭢⭘⒆᳨యࢆ⏝࠸ࡓ᳨ウ࡛ࡣ㸪0LHDS ࡣ⣽⬊㉁Ⓨ⌧ࡀㄆࡵࡽࢀ㸪Ⰻᛶ⭘⒆ )$ ࡼࡾࡶ '&,6㸪,'& ᝏᛶᗘࡀ㧗ࡲࡿࡘࢀ࡚ 0LHDS ࡢⓎ⌧ ࡣ᭷ពపୗࡋ࡚࠸ࡓࠋS%1,31,;0LHDS ࢆࡋࡓ 04& ⤒㊰ࡣ㸪ங⟶⒴ᝈ⪅ࡢ 㸣࡛◚⥢ࡋ࡚࠸ ࡓࡀ㸪≉ 0LHDS ࣉ࣮ࣟࣔࢱ࣮㡿ᇦࡢ࣓ࢳࣝ࠾ࡼࡧ S 㑇ఏᏊࡢኚ␗ࢆ᮶ࡋࡓࡣ㸪7ULSOH QHJDWLYH㸪+(5W\SH㸪/XPLQDO% ࠸ࡗࡓᝏᛶᗘࡢ㧗࠸⭘⒆࡛࠶ࡾ㸪ࡑࡢணᚋࡣ᭷ពⰋ࡛࠶ࡗ ࡓࠋᮏ◊✲⤖ᯝࡼࡾ㸪0LHDS ࡣங⭢⣽⬊ࡢᝏᛶ㌿࡞ࡽࡧ⒴ࡢᝏᛶᗘ῝ࡃ㛵ࡋ࡚࠸ࡿྍ⬟ᛶ ࡀ♧၀ࡉࢀࡓࠋ ࠙⤖ㄽࠚ 㻹㼕㼑㼍㼜 䛿ங⭢⭘⒆䛻䛚䛔䛶䜒㸪⣽⬊䛾ᝏᛶ䛒䜛䛔䛿ᝏᛶ㐍⾜䜢㜼Ṇ䛩䜛⒴ᢚไ㑇ఏᏊ䛷䛒䜛䚹 ㄽ ᩥ ᑂ ᰝ ࡢ ⤖ ᯝ ࡢ せ ᪨ ⏦ㄳ⪅ 6,4,1*$2:$ ࡣ㸪࣑ࢺࢥࣥࢻࣜࡢရ㉁⟶⌮ᶵᵓ࠾࠸࡚㔜せ࡞ᙺࢆᯝࡓࡍ 0LHDS ࡀ㸪 ࣄࢺங⒴⣽⬊ᰴ࢝ࢫࣃ࣮ࢮ౫Ꮡᛶࡢ࣏ࢺ࣮ࢩࢫࢆㄏᑟࡍࡿࡇࢆド᫂ࡋࡓࠋࡲࡓ 0LHDS ࡢⓎ⌧ ࡀங⭢⭘⒆䛾ᝏᛶ䛻క䛔పୗ䛩䜛䛣䛸㸪S0LHDS ⤒㊰ࡢ◚⥢࣭␗ᖖࡀங⭢⭘⒆䛾ᝏᛶᗘ䛻῝䛟㛵 䛧䠈ங⟶⒴ᝈ⪅ࡢணᚋࢆつᐃࡍࡿྍ⬟ᛶ䜢᫂䜙䛛䛻䛧䛯䚹⭘⒆⣽⬊ᑐࡍࡿ 0LHDS ࡢ᪂ࡓ࡞ࡿᶵ⬟ࡸ㸪 ྠศᏊࡢங⭢⭘⒆࠾ࡅࡿⓎ⌧ࡢព⩏ࢆ♧ࡋࡓᮏ◊✲⤖ᯝࡢ⮫ᗋⓗ㔜せᛶࡣ㧗ࡃ㸪ᚋࡢங⭢⭘⒆ ᏛࡢⓎᒎ࣭㐍Ṍᑡ࡞ࡽࡎᐤࡍࡿࡶࡢㄆࡵࡿࠋ 㹙ㄽᩥබ⾲ㄅ㹛
Siqin Gaowa㸪 Manabu Futamura㸪 Masayuki Tsuneki㸪 Hiroki Kamino㸪 Jesse Y. Tajima㸪 Ryutaro Mori㸪 Hirofumi Arakawa㸪 Kazuhiro Yoshida : Possible role of p53/Mieap-regulated mitochondrial quality control as a tumor suppressor in human breast cancer.
